The present invention relates to novel compounds and methods for the treatment of glaucoma and ocular hypertension. In particular, the present invention relates to the use of certain 13-aza analogs of F series prostaglandins to treat glaucoma and ocular hypertension.
Glaucoma is a progressive disease which leads to optic nerve damage and, ultimately, total loss of vision. The causes of this disease have been the subject of extensive studies for many years, but are still not fully understood. The principal symptom of and/or risk factor for the disease is elevated intraocular pressure or ocular hypertension due to excess aqueous humor in the anterior chamber of the eye.
The causes of aqueous humor accumulation in the anterior chamber are not fully understood. It is known that elevated intraocular pressure (xe2x80x9cIOPxe2x80x9d) can be at least partially controlled by administering drugs which either reduce the production of aqueous humor within the eye, such as beta-blockers and carbonic anhydrase inhibitors, or increase the outflow of aqueous humor from the eye, such as miotics and sympathomimetics.
Most types of drugs conventionally used to treat glaucoma have potentially serious side effects. Miotics such as pilocarpine can cause blurring of vision and other visual side effects, which may lead either to decreased patient compliance or to termination of therapy. Systemically administered carbonic anhydrase inhibitors can also cause serious side effects such as nausea, dyspepsia, fatigue, and metabolic acidosis, which side effects can affect patient compliance and/or necessitate the termination of treatment. Another type of drug, beta-blockers, have increasingly become associated with serious pulmonary side effects attributable to their effects on beta-2 receptors in pulmonary tissue. Sympathomimetics, on the other hand, may cause tachycardia, arrhythmia and hypertension. Recently, certain prostaglandins and prostaglandin derivatives have been described in the art a being useful in reducing intraocular pressure. Typically, however, prostaglandin therapy for the treatment of elevated intraocular pressure is attended by undesirable side-effects, such as irritation and hyperemia of varying severity and duration. There is therefore a continuing need for therapies which control elevated intraocular pressure associated with glaucoma without the degree of undesirable side-effects attendant to most conventional therapies.
Prostaglandins are metabolite derivatives of arachidonic acid. Arachidonic acid in the body is converted to prostaglandin G2, which is subsequently converted to prostaglandin H2. Other naturally occurring prostaglandins are derivatives of prostaglandin H2. A number of different types of prostaglandins are known in the art including A, B, C, D, E, F, G, I and J-Series prostaglandins (EP 0 561 073 A1). Of interest in the present invention are compounds which are believed to exhibit IOP lowering mechanisms similar to those exhibited by PGF2xcex1 (an F-series prostaglandin); 
The relationship of PGF2xcex1receptor activation and IOP lowering effects is not well understood. It is believed that PGF2xcex1 receptor activation leads to increased outflow of aqueous humor. Regardless of the mechanism, PGF2xcex1 and certain of its analogs have been shown to lower IOP (Giuffre, The Effects of Prostaglandin F2xcex1 the Human Eye, Graefe""s Archive Ophthalmology, volume 222, pages 139-141 (1985); and Kerstetter et al., Prostaglandin F2xcex1-1-Isopropylester Lowers Intraocular Pressure Without Decreasing Aqueous Humor Flow, American Journal of Ophthalmology, volume 105, pages 30-34 (1988)). Thus, it has been of interest in the field to develop synthetic PGF2xcex1analogs with IOP lowering efficacy.
Synthetic PGF2xcex1-type analogs have been pursued in the art (Graefe""s Archive Ophthalmology, volume 229, pages 411-413 (1991)). Though PGF2xcex1-type molecules lower IOP, a number of these types of molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing. Such effects include an initial increase in IOP, breakdown of the blood aqueous barrier and conjunctival hyperemia (Alm, The Potential of Prostaglandin Derivatives in Glaucoma Therapy, Current Opinion in Ophthalmology, volume 4, No. 11, pages 44-50 (1993)).
Based on the foregoing, a need exists for the development of molecules that may activate the PGF2xcex1 receptor yielding a more efficacious lowering of IOP, while exhibiting fewer or reduced side effects.
An agent which exhibits comparable or improved efficacy, but with reduced side effects when compared to other agents, is said to have an improved therapeutic profile. It is an object of this invention to provide a class of IOP lowering agents with an improved therapeutic profile over PGF2xcex1 and methods of their use. It has now unexpectedly been discovered that the presently claimed 13-aza analogs of prostaglandins meet this objective. Although several 13-aza compounds of the present invention of formula i below are known [Favara, D.; et. al. Prostaglandins 1983, 25(3), 311; and U.S. Pat. Nos. 4,189,606 and 4,182,903 the disclosures of which are by this reference incorporated herein], we are aware of no reports teaching or suggesting their IOP-lowering abilities. 
wherein: M=H, alkyl, or cation; R1=acyl or H; R=H or alkyl; X=CH2O or (CH2)n, where n=0-4; and Ar=substituted or unsubstituted phenyl.
The present invention is directed to novel compounds and compositions, and methods of their use, as well as the novel use of some known compounds, in treating glaucoma and ocular hypertension. In particular, the present invention provides 13-aza prostaglandins having functional PGF2xcex1receptor agonist activity, and methods of their use in treating glaucoma and ocular hypertension.
It has unexpectedly been found that 13-aza prostaglandin analogs of the present invention exhibit an improved therapeutic profile in the treatment of glaucoma and ocular hypertension when compared to natural prostaglandins and many of their known analogs. The 13-aza prostaglandin analogs of the present invention may also be used to treat optic nerve disorder by retarding visual field loss or improving visual acuity in the manner described in U.S. Pat. No. 5,773,471, the disclosure of which is incorporated herein by this reference.
It is further contemplated that the compounds of the present inventions can be used with other medicaments known to be useful in the treatment of glaucoma or ocular hypertension, either separately or in combination. For example, the 13-aza prostaglandin analogs of the present invention can be combined with (i) beta-blockers, such as timolol, betaxolol, levobunolol and the like (see U.S. Pat. No. 4,952,581); (ii) carbonic anhydrase inhibitors, such as brinzolamide; (iii) adrenergic agonists including clonidine derivative;, such as apraclonidine or brimonidine (see U.S. Pat. No. 5,811,443); and (iv) cholinergic agonists, such as pilocarpine. The disclosures of U.S. Pat. Nos. 4,952,581 and 5,811,443 are incorporated herein by this reference.
The 13-aza prostaglandin analogs of the present invention have the following formula I: 
wherein:
R1=CO2R, CONR4R5, CH2OR6, or CH2NR7R8, where:
R=H, alkyl, cationic salt moiety, or CO2R forms a pharmaceutically acceptable ester moiety;
R4, R5=same or different=H or alkyl;
R6=H, acyl, or alkyl; and
R7, R8=same or different=H, acyl, or alkyl; with the proviso that if one of R7, R8=acyl, then the other=H or alkyl;
n=0 or2;
R2, R3=same or different=H, alkyl, or acyl;
xe2x80x94xe2x80x94xe2x80x94=single or non-cumulated double bond;
J=O or H and H;
R9=H, alkyl, acyl, or SO2Ar, where Ar=a phenyl ring optionally substituted with hydroxy, acyloxy, alkoxy, alkoxycarbonyl, halo, trihalomethyl, amino, acylamino, or aminoacyl;
one of C,D=H, and the other=F,OH, acyloxy, or alkoxy;
or Cxe2x80x94Dxe2x95x90O(CH2)2O or double bond O;
with the proviso that if J=O then R9=H or alkyl, and one of C, D=H, and the other=F, OH, acyloxy, or alkoxy;
X=(CH2)q, or (CH2)qO; where q=0-6; and
Y=a phenyl ring optionally substituted with alkyl, halo, trihalomethyl, alkoxy, acyl, acyloxy, alkylamino, acylamino, or OH;
or Xxe2x80x94Y=(CH2)pY1, where p=0-6 and 
wherein:
W=CH2, O, S(O)m, NR10, CH2CH2, CHxe2x95x90CH, CH2O, CH2S(O)m, CHxe2x95x90N, or CH2NR10, where m=0-2, and R10=H, alkyl, or acyl;
Z=H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino, acylamino, or OH; and
xe2x80x94xe2x80x94xe2x80x94=single or double bond.
As used herein, the term xe2x80x9cpharmaceutically acceptable esterxe2x80x9d means any ester that would be suitable for therapeutic administration to a patient by any conventional means without significant deleterious health consequences; and xe2x80x9cophthalmically acceptable esterxe2x80x9d means any pharmaceutically acceptable ester that would be suitable for ophthalmic application, i.e. non-toxic and non-irritating. Preferred are alkyl esters. Most preferred are C2-C4 alkyl esters, and especially isopropyl esters.
Preferred compounds for use in the present invention are those of formula I above, wherein:
R1=CO2R, where R=H, or CO2R forms an ophthalmically acceptable ester moiety;
n=0;
R2=R3=H;
xe2x80x94xe2x80x94xe2x80x94=single or non-cumulated double bond, with the proviso that a double bond between carbons 4 and 5 may not be of the trans configuration:
J=O, or H and H;
R9=H when J=O; and R9=H or acyl when J=H and H;
one of C, D=H, and the other=OH;
X=(CH2)2 or CH2O; and
Y=phenyl, optionally substituted with halo or trihalomethyl; or
Xxe2x80x94Y=Y1 where 
Most preferred for use in the present invention are the following compounds:
The compounds of the present invention believed to be novel are those compounds of formula I wherein:
R1=CO2R, CONR4R5, CH2OR6, or CH2NR7R8, where:
R=H, alkyl, cationic salt moiety, or CO2R forms a pharmaceutically acceptable ester moiety;
R4, R5=same or different=H or alkyl;
R6=H, acyl, or alkyl; and
R7, R8=same or different=H, acyl, or alkyl; with the proviso that if one of R7, R8=acyl, then the other=H or alkyl;
n=0 or 2;
R2, R3=same or different=H, alkyl, or acyl;
xe2x80x94xe2x80x94xe2x80x94=single or non-cumulated double bond;
J=O or H and H;
R9=H, alkyl, acyl, or SO2Ar, where Ar=a phenyl ring optionally substituted with hydroxy, acyloxy, alkoxy, alkoxycarbonyl, halo, trihalomethyl, amino, acylamino, or aminoacyl;
one of C, D=H, the other=F, OH, acyloxy, or alkoxy; or
Cxe2x80x94Dxe2x95x90O(CH2)2O or double bonded O;
with the proviso that if J=O, then R9=H or alkyl, one of C, D=H, and the other=F, OH, acyloxy, or alkoxy;
X=(CH2)q or (CH2)qO, where q=0-6; and
Y=a phenyl ring optionally substituted with alkyl, halo, trihalomethyl, alkoxy, acyl, acyloxy, alkylamino, acylamino, or OH; or
Xxe2x80x94Y=(CH2)pY1, where p=0-6 and 
wherein:
W=CH2, O, S(O)m, NR10, CH2CH2, CHxe2x95x90CH, CH2O, CH2S(O)m, CHxe2x95x90N, or CH2NR10, where m=0.2; and R10=H, alkyl, acyl;
Z=H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino, acylamino, or OH; and
xe2x80x94xe2x80x94xe2x80x94=single or double bond;
with the proviso that the compounds of formula I possessing all of the following limitations be excluded:
R1=CO2R, where R=H, alkyl, or cationic salt moiety;
n=0;
xe2x80x94xe2x80x94xe2x80x94=a single bond between carbons 4 and 5, and a cis double bond between carbons 5 and 6;
R2, R3=H or acyl;
R9=H;
J=O;
one of C,D=H, and the other=OH or alkoxy;
X=(CH2)q or (CH2)qO, where q=0-6; and
Y=a phenyl ring optionally substituted with alkyl, halo, trihalomethyl, alkoxy, acyl, acyloxy, alkylamino, acylamino, or OH.
Preferred novel compounds of the invention include those of formula I, wherein:
R1=CO2R, where R=H or CO2R forms a pharmaceutically acceptable ester moiety;
n=0;
xe2x80x94xe2x80x94xe2x80x94=a single bond between carbons 5 and 6, and a cis double bond between carbons 4 and 5; or a single bond between carbons 4 and 5, and a cis double bond between carbons 5 and 6;
R2=R3=H;
R9=H;
J=O or H and H;
one of C,D=H, and the other=OH;
X=CH2O or CH2CH2; and
Y=phenyl, optionally substituted with halo or trihalomethyl; or
Xxe2x80x94Y=Y1, where 
with the proviso that the compounds of formula I possessing all of the following limitations be excluded, wherein:
R1=CO2R, where R=H;
n=0;
xe2x80x94xe2x80x94xe2x80x94=a single bond between carbons 4 and 5, and a cis double bond between carbons 5 and 6;
R2=R3=H;
R9=H;
J=O;
one of C,D=H, and the other=OH;
X=CH2O or CH2CH2; and
Y=phenyl, optionally substituted with halo or trihalomethyl.
Chemical Definitions
The term xe2x80x9cacylxe2x80x9d represents a group that is linked by a carbon atom that has a double bond to an oxygen atom and single bond to another carbon atom.
The term xe2x80x9cacylaminoxe2x80x9d represents a group that is linked by an amino atom that is connected to a carbon atom has a double bond to an oxygen group and a single bond to a carbon atom or hydrogen atom.
The term xe2x80x9cacyloxyxe2x80x9d represents a group that is linked by an oxygen atom that is connected to a carbon that has a double bond to an oxygen atom and single bond to another carbon atom.
The term xe2x80x9calkenylxe2x80x9d includes straight or branched chain hydrocarbon groups having 1 to 15 carbon atoms with at least one carbon-carbon double bond. The chain hydrogens may be substituted with other groups, such as halogen. Preferred straight or branched alkeny groups include, allyl, 1-butenyl, 1 -methyl-2-propenyl and 4-pentenyl.
The term xe2x80x9calkoxyxe2x80x9d represents an alkyl group attached through an oxygen linkage.
The term xe2x80x9calkylxe2x80x9d includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms. The alkyl groups may be substituted with other groups, such as halogen, hydroxyl or alkoxy. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl.
The term xe2x80x9calkylaminoxe2x80x9d represents an alkyl group attached through a nitrogen linkage.
The term xe2x80x9calkynylxe2x80x9d includes straight or branched chain hydrocarbon groups having 1 to 15 carbon atoms with at least one carbon-carbon triple bond. The chain hydrogens may be substituted with other groups, such as halogen. Preferred straight or branched alkynyl groups include, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl and 2-pentynyl.
The term xe2x80x9carylxe2x80x9d refers to carbon-based rings which are aromatic. The rings may be isolated, such as phenyl, or fused, such as naphthyl. The ring hydrogens may be substituted with other groups, such as lower alkyl, or halogen.
The term xe2x80x9ccarbonylxe2x80x9d represents a group that has a carbon atom that has a double bond to an oxygen atom.
The term xe2x80x9ccarbonylalkoxyxe2x80x9d represents a group that is linked by a carbon atom that has a double bond to an oxygen atom and a single bond to an alkoxy group.
The term xe2x80x9ccationic salt moietyxe2x80x9d includes alkali and alkaline earth metal salts as well as ammonium salts.
The term xe2x80x9ccarbonyloxylxe2x80x9d represents a group that is linked by a carbon atom that has a double bond to an oxygen atom and a single bond to a second oxygen atom.
The term xe2x80x9ccycloalkylxe2x80x9d includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more rings, which can be fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl or lower alkyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term xe2x80x9cdialkylaminoxe2x80x9d represents two alkyl groups attached through a nitrogen linkage.
The term xe2x80x9chalogenxe2x80x9d and xe2x80x9chaloxe2x80x9d represents fluoro, chloro, bromo, or iodo.
The term xe2x80x9cheteroarylxe2x80x9d refers to aromatic hydrocarbon rings which contain at least one heteroatom such as O, S, or N in the ring. Heteroaryl rings may be isolated, with 5 to 6 ring atoms, or fused, with 8 to 10 atoms. The heteroaryl ring(s) hydrogens or heteroatoms with open valency may be substituted with other groups, such as lower alkyl or halogen. Examples of heteroaryl groups include imidazole, pyridine, indole, quinoline, furan, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, and dihydrobenzindole.
The term xe2x80x9clower alkylxe2x80x9d represents alkyl groups containing one to six carbons (C1-C6).
In the foregoing illustrations, as well as those provided hereinafter, wavy line attachments indicate that the configuration may be either alpha (xcex1) or beta (xcex2). The carbon numbering is as indicated in formula I, even when n=2. Dashed lines on bonds indicate a single or double bond. Two solid lines between carbons specify the configuration of the relevant double bond. Hatched lines indicate the xcex1 configuration. A solid triangular line indicates the xcex2 configuration.
In the following Examples 1-4, the following standard abbreviations are used: g=grams (mg=milligrams); mol=moles (mmol=millimoles); mL=milliliters; mm Hg=millimeters of mercury; mp=melting point; bp=boiling point; h=hours, and min=minutes. In addition, xe2x80x9cNMRxe2x80x9d refers to nuclear magnetic resonance spectroscopy and xe2x80x9cMSxe2x80x9d refers to mass spectrometry.